Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism

Optineurin功能障碍通过一种新的分子机制诱导正常眼压青光眼的神经变性

基本信息

批准号：
10372873
负责人：
Yang Hu
金额：
$ 54.57万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10372873
关键词：
Amyotrophic Lateral Sclerosis Animal Model Autophagocytosis Axon Axonal Transport Biochemical Biological Assay Biotin Blindness Cell Death Cytokine Signaling Data Environment Failure Functional disorder Gene Mutation Genes Glaucoma Goals Histologic Human Hybrids Impairment Inherited Intervention Link Mediating Mitochondria Modeling Molecular Monitor Morphology Mus Mutation Nerve Degeneration Neurons Ocular Hypertension Optic Nerve Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physiologic Intraocular Pressure Play Population Positioning Attribute Proteins Retina Retinal Ganglion Cells Role Scientist Structure Testing Therapeutic Time Transgenic Mice Vacuum Vesicle Yeasts axonal degeneration axonopathy base cDNA Library causal variant cellular imaging experimental study gene function in vivo mouse model mutant neural repair neuronal cell body neuronal survival neuroprotection new therapeutic target novel optic nerve disorder overexpression receptor retinal axon syntaphilin tool trafficking

项目摘要

PROJECT SUMMARY Normal tension glaucoma (NTG) is characterized by optic neuropathy with progressive retinal ganglion cell (RGC) death and optic nerve (ON) degeneration but in the absence of intraocular pressure (IOP) elevation. All current glaucoma treatments are to lower IOP and are less effective in NTG patients. The primary reasons for the therapeutic vacuum are the limited understanding of the molecular mechanisms of IOP-independent glaucomatous degeneration and the lack of a practical and effective NTG animal model. Causal mutations in the optineurin gene (OPTN) have been found in familial and sporadic NTG. Interestingly, OPTN mutations also cause inherited forms of another CNS axonopathy, amyotrophic lateral sclerosis (ALS), indicating a common degenerative machinery that can be activated by dysfunctional OPTN in vulnerable CNS neuronal populations. However, although OPTN has been extensively studied and its various roles in autophagy, cytokine signaling, and vesicle trafficking have been found, the pathophysiology role of OPTN in CNS neurodegeneration are far from clear. We have recently established a highly efficient NTG mouse model by truncating OPTN gene in RGCs specifically, which presents significant RGCs and ON degeneration within weeks. Using this novel NTG model, we propose to investigate how OPTN mutation causes neurodegeneration in vivo through validating and characterizing OPTN-interacting proteins in RGCs and ON. Through these studies, we will generate essential information to uncover novel molecular mechanisms of glaucomatous neurodegeneration related with OPTN that may be also shared by ALS and other CNS axonopathies, identify novel modifiers of RGC/ON neurodegeneration, and provide valuable tools and animal models to develop neuroprotection therapies.

项目概要正常眼压性青光眼 (NTG) 的特征是伴有进展性视网膜神经节细胞的视神经病变（RGC）死亡和视神经（ON）变性，但没有眼压（IOP）升高。全部目前的青光眼治疗主要是降低眼压，对 NTG 患者效果较差。主要原因治疗真空是对 IOP 独立分子机制的有限了解青光眼变性且缺乏实用有效的NTG动物模型。因果突变 optineurin 基因 (OPTN) 已在家族性和散发性 NTG 中发现。有趣的是，OPTN 突变也导致另一种中枢神经系统轴突病的遗传形式，即肌萎缩侧索硬化症（ALS），这表明一种常见的脆弱的中枢神经系统神经元群中功能失调的 OPTN 可以激活退行性机制。然而，尽管 OPTN 已被广泛研究及其在自噬、细胞因子信号传导中的各种作用，和囊泡运输已被发现，OPTN在中枢神经系统神经变性中的病理生理学作用尚不清楚从明确。我们最近通过截断RGC中的OPTN基因建立了高效的NTG小鼠模型具体来说，它会在几周内呈现出明显的 RGC 和 ON 变性。使用这种新颖的 NTG 模型，我们建议通过验证和研究 OPTN 突变如何导致体内神经变性表征 RGC 和 ON 中的 OPTN 相互作用蛋白。通过这些研究，我们将产生必要的揭示与 OPTN 相关的青光眼神经变性的新分子机制的信息 ALS 和其他 CNS 轴突病也可能具有相同的特征，确定 RGC/ON 的新修饰因子神经退行性变，并为开发神经保护疗法提供有价值的工具和动物模型。